The anti-cancer drug taxol 1 has shown excellent clinical activity against ovarian cancer and breast cancer and has also shown good activity against non-small cell lung cancer in preliminary studies. See "Taxol: A Unique Antineoplastic Agent With Significant Activity in an Advanced Ovarian Epithelial Neoplasms," Ann. Intern. Med., 111, 273-279 (1989), and "Phase II Trial of Taxol, an Active Drug in the Treatment of Metastatic Breast Cancer," J. Natl. Cancer Inst., 83, 1797-1805 (1991). Taxol was first isolated and its structure reported by Wani, et al, in "Plant Anti-Tumor Agents. VI. The Isolation and Structure of Taxol. A Novel Anti-Leukemic and Anti-Tumor Agent From Taxus Brevifolia," J. Am. Chem. Soc., 1971, 93, 2325. Taxol is found in the stem bark of the western yew, Taxus brevifolia, as well as in T. baccata and T. cuspidata. All references cited herein are incorporated by reference as if reproduced in full below. ##STR2##
The preparation of analogues of taxol is an important endeavor, especially in view of taxol's clinical activity and its limited supply. The preparation of analogues might result in the synthesis of compounds with greater potency than taxol (thus reducing the need for the drug), compounds with superior bioavailability, or compounds which are easier to synthesize than taxol from readily available sources. Indeed, the synthesis of the taxol analogue taxotere 2, which differs from taxol only in the nature of the N-acyl substituent and in the absence of the 10-acetyl group, indicates the usefulness of this approach, since taxotere is reported to be approximately twice as active as taxol in some assays. See "Chemical Studies of 10-deacetyl Baccatin III. Hemisynthesis of Taxol Derivatives." Tetrahedron, 42, 4451-4460 (1986), and "Studies With RP56976 (taxotere): A Semi-Synthetic Analogue of Taxol." J. Natl. Cancer Inst., 83, 288-291 (1991). ##STR3##
Numerous analogues of taxol having modifications of the C-13 side chain have been prepared. See U.S. Pat. No. 5,059,699. Many of the derivatives bearing modifications on the C-13 side chain have demonstrated anti-cancer activity. See for example: "The Chemistry of Taxol," Pharmac. Ther., 52, 1-34 (1991) and references therein, "Synthesis and Evaluation of some water-soluble prodrugs and derivatives of taxol with anti-tumor activity, J. Med, Chem., 35, 145-151 (1992), "Biologically Active Taxol Analogues with Deleted A-Ring Side Chain Substituents and Variable C-2' Configurations," J. Med. Chem., 34, 1176-1184 (1991), "Relationships Between the Structure of Taxol Analogues and Their Antimitotic Activity" J. Med. Chem., 34, 992-998 (1991).
Factors that contribute to the paucity of taxol congeners relative to their importance as anti-cancer agents include: the large size and complexity of these compounds, the presence of multiple reactive sites, and the presence of many stereospecific sites, which makes synthesis of even close analogues difficult. The large number of possible reaction mechanisms for even the simplest reactions leads to unpredictability of new reactions.
Although taxol has exhibited promising antineoplastic activity, there is a need for compounds which have even greater antineoplastic activity. It is believed that, by altering certain portions of the taxol structure, compounds with improved antineoplastic activity can be produced. Nevertheless, the aforementioned synthetic difficulties have prevented or at least slowed the development of more than only a few compounds, such as taxotere, which have similar or greater activity than taxol. Since it is believed that the tetracyclic taxane nucleus contributes to the antineoplastic activity of compounds incorporating same, it is desired to alter the ring substituents in order to develop derivatives of taxol and taxol analogues. Based on the previously noted studies, it is anticipated that such derivatives will have antineoplastic activity. Nevertheless, the complexity of taxol and its analogues makes it difficult to selectively alter certain substituents on the molecule. In particular, it has been previously impossible to selectively deacylate the C-2 position of taxol, and to produce taxol analogues modified at the C-2 position. Thus, there is a need for C-2 debenzoylated taxol analogues and congeners modified at the C-2 position, having antineoplastic activity, and intermediates thereof. There is also a need for methods for producing same and for using same to treat cancer. Since taxol and taxol analogues have low water solubility, there is a need to produce taxol analogues modified at the C-2 position having improved water solubility to aid in administration to cancer patients.